Method for the preparation of a pharmaceutical composition comprising 5-aminosalicylic acid for use in treatment of ulcerative colitis and Crohn&#39;s disease

ABSTRACT

The present invention concerns a new method of preparing granules comprising 5-aminosalicylic acid and a new method of preparing a pharmaceutical composition for the treatment of ulcerative colitis or Crohn&#39;s disease by oral administration comprising as active ingredient 5-aminosalicylic acid.

This application claims the benefit of U.S. Provisional Application No.60/328,831, filed Oct. 15, 2001, as well as International ApplicationNo. PCT/DK01/00677, filed Oct. 15, 2001.

The present invention relates to a method of preparing a pharmaceuticalcomposition useful for the treatment of ulcerative colitis and Crohn'sdisease, currently denominated “inflammatory bowel diseases” (IBD). Moreparticular, the invention relates to a new method of producing granulescomprising 5-aminosalicylic acid (5-ASA) for use in the preparation ofsolid oral dosage forms.

Ulcerative colitis is a chronic inflammatory disease of the colon ofunknown etiology. In its acute stages it resembles an infectiousdisease, but no microorganism has been definitively established as itscause. The disease causes inflammations of the mucosa of the colon, withextension to the submucosa in severe cases. Typically, not only thecolon, but also the rectum is attacked, but only rarely is the ileuminvolved. The ulcer formation and its extent vary with the developmentalstage of the disease, but can often be determined macroscopically(sigmoidoscopy and colonoscopy).

The related disease, Crohn's disease, also known as regional enteritisor colitis granulomatosa, is most frequently located in the smallintestine (small bowel), especially in the ileum, but may also affectthe jejunum and any part of the colon, including the rectum. In thelatter case the differentiation of Crohn's disease from ulcerativecolitis gives rise to great diagnostic problems. Generally, theinflammation differs from that of ulcerative colitis by progressing tolayers deeper than the mucosa and affecting the epithelium to a lesserdegree.

Both diseases have become increasingly frequent especially in thedeveloped countries. In the United States, the incidence of theulcerative colitis is 5-15 cases per 100,000 inhabitants, whereas theincidence is approximately 5 per 100,000 inhabitants in the case ofCrohn's disease, the figures continue to increase. Therefore, treatmentof IBD has become an important problem of modern medicine.

WO 81/02671 discloses a pharmaceutical composition for the treatment ofIBD by oral administration. The invention was based on findings that anoral administration of 5-ASA as the free acid or in the form of itssalts or esters has a useful therapeutic effect on ulcerative colitis,in particular when administered in the form of sustained-releasetablets. WO 81/02671 further discloses a method for the preparation ofsustained release tablets comprising the steps of preparing granulesfrom 5-ASA and a solution of polyvinylpyrrolidone in isopropanol,evaporating the solvent, coating the granules with ethyl cellulose andformulating the coated granules into tablets.

U.S. Pat. No. 4,632,921 further discloses a process for the productionof readily soluble 5-ASA preparations by mixing 5-ASA withphysiologically and toxicologically acceptable, basic auxiliaries and/orbuffer mixtures, which in a 1% aqueous solution give pH-values in therange from 8 to 12, and the mixture obtained is processed in knownmanner to form tablets, film tablets, dragees, capsules orsuppositories, i.e. a stable and readily soluble pharmaceuticalpreparation for oral or rectal application based on 5-ASA for use in thetreatment of IBD.

U.S. Pat. No. 4,880,794 discloses a method for the treatment of IBDcomprising orally administering an effective amount of a compositionconsisting essentially of a pharmaceutically acceptable salt of free5-ASA in admixture with a pharmaceutically acceptable carrier which willcontrol the release of said effective amount of said salt of 5-ASA to beadministered according to the actual site of said disease.

U.S. Pat. No. 4,960,765 further discloses a method for the treatment ofIBD comprising orally administering an effective amount of a compositionconsisting essentially of an ester of free 5-ASA in admixture with apharmaceutically acceptable carrier so as to delay the release of 5-ASAfrom said composition essentially until it reaches the colon of thepatient. Release dependent on pH in the colon is achieved by using acoating resulting in a gradual release of 5-ASA. The particles arecoated with ethyl cellulose.

U.S. Pat. No. 4,980,173 discloses a method for the preparation ofsustained-release tablets useful for the treatment of IBD by preparing agranulate containing 5-ASA and PVP using an organic solvent. Thegranulate is coated with a pH sensitive coating (cellulose derivative).A second non-coated granulate is prepared and mixed with the coatedgranulate and a lubricant.

U.S. Pat. No. 5,013,727 discloses a pharmaceutical compositioncontaining as active ingredient 5-ASA or a pharmaceutically acceptablesalt or ester thereof allowing the treatment of IBD by oraladministration. A particular slow-release tablet formulation and itspreparation are disclosed.

U.S. Pat. No. 5,541,170 further discloses a pharmaceutical compositionand method for the treatment of IBD by oral administration. Theinvention may be a solid dosage form, such as a capsule or tablet,containing a pharmacologically active agent coated with an anionicpolymer, which is insoluble in gastric juice and in intestinal juicebelow pH 7 but soluble in colonic intestinal juice, in a sufficientamount that the oral dosage form remains intact until it reaches thecolon. The preferred anionic polymer is a partly methyl esterifiedmethacrylic acid polymer in which the ratio of free carboxylic groups toester groups is about 1:2. The invention has particular application todosage forms of prednisolone and salts thereof, indomethacin, ibuprofen,and, especially, 5-amino-salicylic acid.

5-ASA has proven to be very useful in treating ulcerative colitis andCrohn's disease. Different 5-ASA prolonged release 250 mg and later on500 mg tablets, e.g. Pentasa®, have been registered in differentcountries for a number of years.

All the prior art concerning 5-ASA tablet formulations disclose the useof isopropyl alcohol as the main solvent for the binder in thepreparation of 5-ASA granules. It is nowhere disclosed that anothersolvent, such as water, for the purpose of producing tablets, mayreplace the organic solvent.

WO 97/23199 discloses a modified release composition for treatment ofIBD comprising spherical granules comprising a core of 5-ASA and aspheronization aid prepared in water as a solvent and coated with a ratelimiting barrier material. The composition results in a minor release of5-ASA in the stomach and the granules may be packed in sachets. Thesegranules are not suitable for use in tablets.

Due to the still increasing demand for 5-ASA containing pharmaceuticals,there is a need for improving the manufacturing process of 5-ASAcontaining tablets.

SUMMARY OF THE INVENTION

As each 5-ASA containing tablet or dose contains a relative large amountof the active ingredient in order to maximise the therapeutic effect,large amounts of material have to be handled at the productionfacilities.

The ever-growing market for 5-ASA containing medicaments has lead to ademand for improvements of the hitherto used method for the productionof 5-ASA-containing tablets. In the present invention, the improvementsprovide for a better, faster and less costly method for the productionof 5-ASA containing tablets without loss of quality and bioavailabilityof the 5-ASA.

The aim of the invention is to obtain an improved composition ofextruded granules for use in Pentasa® or similar tablets. The granulesshould be strong and smooth, tolerate the different processing stepsduring production and be produced with a narrow and reproducibleparticle size distribution.

Surprisingly, an improvement could be achieved without changing the mainprinciple in the existing manufacturing process.

5-ASA comprising tablets prepared according to the present invention arestill produced by first mixing the active ingredient 5-aminosalicylicacid with a solution of a pharmaceutically acceptable binder, e.g.polyvinylpyrrolidone (PVP), in a solvent. This mixture is extruded intogranules, which are dried in a fluid bed. After drying the granules aremilled and sieved before the granules are ready for coating, for examplein a fluid bed. In the coating process a polymer is coated upon thegranules until the desired dissolution rate profile is obtained. Thecoated granules are then mixed with tablet excipients and compressedinto tablets.

In one aspect of the invention, it has surprisingly been found that theorganic solvent used in the existing method may advantageously bereplaced partly or totally by water.

U.S. Pat. No. Re 33,239 teaches that 5-ASA has a poor stability beingsensitive to moisture and light. Said patent discloses a pharmaceuticalcomposition comprising 5-ASA in solution or as a suspension togetherwith additives in order to stabilise the 5-ASA. Moreover, thecomposition is to be packed in a diffusion tight light-imperviouspackage under an inert gas.

Thus, the use of water as the main solvent is contrary to the teachingconcerning formulation of 5-ASA tablets. In the existing method, theproblem with stability related to moisture is avoided by the use of anorganic solvent as the main solvent. Surprisingly, it has now turned outthat water may indeed be used as the major part of the solvent in thepreparation of granules containing 5-ASA for use in tablet formulations,essentially without affecting the stability of 5-ASA. It is believedthat the use of a continuous drying process in e.g. a fluid bed isinstrumental for obtaining a stable product allowing for a quick andgentle drying process as well as protecting the product against light.

In WO 97/23199 water was used as a solvent in the production of thespherical granules, which, however, comprise a different binder and aretreated immediately in a spheronization and drying process. Thespherical granules are not optimal for use in tablets due tosegregation.

It has now surprisingly turned out that replacement of all or a part ofthe organic solvent by water leads to a process in which granules with anarrower particle size distribution are produced and that the resultinggranules are stronger with a smoother surface. These improvements leadto an increased yield of tablets from the process.

Furthermore, the smooth surface of the granules results in the coatingprocess becoming more reproducible and reduces the amount of coatingmaterial used in the process.

In addition to the above improvements of the product, a reduction in theuse of organic solvents is the result, leading to a reduced hazard tothe operators in the production facilities and to the environment aswell as a reduction in the overall content of organic solvent in thefinal product. Additionally, the costs of organic solvents may be highlyreduced.

In a second aspect of the present invention, the preparation of granulesfrom the wet mass of 5-ASA and the binder form part of a continuousproduction line for the production of 5-ASA granules.

In a third aspect of the present invention, the method of preparinggranules forms part of a method of preparing 5-ASA tablets.

As discussed above, it may be desirable to handle large amounts ofmaterial in the production line. The production line may thereforeadvantageously be designed to be continuous, where 5-ASA is mixed withthe aqueous PVP solution before or in the extruder, and the resultinggranules are dried, milled and sieved in one continuous process. Thefeeding of the individual ingredients is regulated continuously, e.g. byway of weight measurements of the different feeds as a part of theproduction line.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows enlarged photo of granules after sieving preparedaccording to the existing process. (Batch no. KGGU 405R)

FIG. 1B shows particle size distribution (sieve analysis) after sievingof granules prepared according to the existing process. (Batch no. KGGU405R)

FIG. 2A shows enlarged photo of granules after sieving preparedaccording to the existing process. (Batch no. KGGU 406Q)

FIG. 2B shows particle size distribution (sieve analysis) after sievingof granules prepared according to the existing process. (Batch no. KGGU406Q)

FIG. 3A shows enlarged photo of granules after sieving preparedaccording to the existing process. (Batch no. KGGU 406T)

FIG. 3B shows particle size distribution (sieve analysis) after sievingof granules prepared according to the existing process. (Batch no. KGGU406T)

FIG. 4 shows a flow diagram of the new manufacturing process forPentasa® or similar tablets.

FIG. 5A shows enlarged photo of granules after milling and sievingprepared according to the new process. (Batch no. HLGU311)

FIG. 5B shows particle size distribution (sieve analysis) after millingand sieving of granules prepared according to the new process. (Batchno. HLGU311)

FIG. 6A shows enlarged photo of granules after milling and sievingprepared according to the new process. (Batch no. HLGU315)

FIG. 6B shows particle size distribution (sieve analysis) after millingand sieving of granules prepared according to the new process. (Batchno. HLGU315)

FIG. 7A shows enlarged photo of granules after milling and sievingprepared according to the new process. (Batch no. HLGU319)

FIG. 7B shows particle size distribution (sieve analysis) after millingand sieving of granules prepared according to the new process. (Batchno. HLGU319)

FIG. 8 shows dissolution rate profiles for Pentasa® tablets preparedaccording to the present invention. The figure shows the releasespecifications that the applicant has established for the product inorder to be allowed for sale.

FIG. 9 shows samples taken in the blender to document homogeneity of theblend.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a new method for the preparation of 5-ASAgranules and a new method of producing 5-ASA containing tablets.

The present invention has led to improvements in the overallmanufacturing process of tablets, but also in the production of 5-ASAcontaining granules, improvements that were desired according to the aimof the invention, but which means for success were neither expected, norforeseeable. There are no indications in the prior art that replacementof the organic solvent by water could fulfil the aim of the inventionand thus lead to the desired improvements. The method according to theprior art teaches the use of a solvent comprising about 90% w/wisopropanol and 10% w/w water.

According to the present invention, the solvent suitable for dissolutionof the binder is based on water. The solvent contains at least 50% w/wwater, preferably at least 85% w/w water, more preferably at least 95%w/w and most preferably 100% w/w. The remaining part of the solvent maybe any suitable liquid, such as an organic solvent. The solvent may alsocomprise additives of importance for the process or final product. Suchadditives are within the knowledge of the skilled person. Examples arechelating agents, antioxidants, reducing agents, buffers, pH adjustingagents, co-solvents or any other relevant excipients. Organic solventsmay be present in minor amount as a solubilising agent for theadditives. Preferably the solvent is free of organic solvent.

As each tablet contains a high dose of the active ingredient,5-aminosalicylic acid, it is desirable to handle large amounts ofmaterial at the production facility. The aim of the present invention isthus to improve the existing process, whereby more tablets can beproduced at lower costs, and without compromising on the quality of theproduct.

The main focus of the invention has been to find a method by which it ispossible to obtain granules which are stronger, have a smoother surface,and produced with a narrower particle size distribution than thegranules obtained according to the conventional method.

Stronger granules are very important in the subsequent production stepswhere it is important that the granules are able to withstand stress sothat wear is minimised. Wear will result in fines, which are detrimentalto the coating process due to the variability in surface area that theyintroduce. The fines also result in reduced overall yields.

A smooth surface on the granules is important in order to enablereliable measurement of their surface area and in that way to providefor accurate prediction of the amount of polymer that has to be appliedto the granules in order to obtain the right dissolution rate profile.In addition, the reduced surface area of the granules produced accordingto the present invention allows the amount of coating material to bereduced considerably.

A reproducible particle size distribution for the granules is asimportant as the two previously mentioned parameters in the control ofthe coating process. The particle size distribution is defined by themethod used to perform the sieve analysis. Equipment that may be used inthe analysis may be a number of sieves with different screens placed ontop of each other. The mesh of the first screen is bigger than the meshof the next screen, which is bigger than the mesh of the third screenand so on. An example of meshes that may be used together may be 1400μm, 1250 μm, 1180 μm, 1000 μm, 850 μm, 710 μm, 600 μm and 500 μm meshes.Thus, an 850-1000 μm fraction is that fraction of the granules that areable to pass the 1000 μm mesh, but not the 850 μm mesh.

Results from the development work show that it actually is possible toobtain granules with the desired properties. Surprisingly, the onlychange, compared to the existing process, in order to obtain the desiredproperties, is that the isopropyl alcohol to water ratio of 9:1 used todissolve the PVP in the existing process, is shifted toward more water.The ratio according to the present invention is 1:1 or less. The primaryresults, presented in Table 2, showed that the yield is inverselyproportional with the isopropyl alcohol content. Without wanting to bebound by a theory, it is believed that the rough surface and thevariable size of the granules prepared by the existing method are due todisruption of the granules during the drying step, caused byexplosion-like evaporation of the isopropyl alcohol breaking off largeand small pieces of the granules. The rough surface could also be causedby wear of less strong granules in the drying process. It is believedthat the use of aqueous granulation in combination with a continuousdrying process according to the present invention, leads to a gentlerdrying of the granules, resulting in stronger granules with a smoothersurface.

It is furthermore believed that the improved strength of the granulesleads to the possibility of obtaining predefined reproducible particlesize distributions.

In addition to obtaining the desired properties of the granules asdiscussed above, the results also show some benefits with regards to thenew production process, namely:

-   -   More environmentally acceptable.    -   The environment in the production area being safer for the        operators.    -   Lower production costs.

The avoidance or reduced use of the organic solvent isopropyl alcohol isa huge advantage both in the handling process, where the operators avoidor minimise the risks related to the use of isopropyl alcohol in theproduction area, and for the environment in relation to collection anddisposal of the isopropyl alcohol during and after drying of thegranules. Furthermore, the cost of purchasing and handling isopropylalcohol is reduced. However, if appropriate, an organic solvent may beadded to comprise for up to 50% w/w, however, preferably less than 15%w/w and more preferably less that 5% w/w of the solvent. Most preferred,no organic solvent is used.

Accordingly, the main principles for the manufacturing process of thepresent invention have not been changed when compared to the existingprocess. 5-ASA tablets are produced by first mixing the activeingredient, 5-aminosalicylic acid, with a solution of a binder, e.g.polyvinylpyrrolidone in a solvent, which in the present invention iscomprised of at least 50% w/w water. Preferably the solvent is free oforganic solvent. This wet mass is extruded into granules, which aredried in a continuous fluid bed. After drying, the granules are milledand sieved before the granules are ready for coating in e.g. a fluidbed. In the coating process a polymer is coated upon the granules untilthe desired dissolution rate profile is obtained. The coated granulesare then mixed with tablet excipients and compressed into tablets.

The present invention thus concerns in a first fundamental aspect amethod for the preparation of granules comprising 5-aminosalicylic acid(5-ASA) or a pharmaceutically acceptable salt or ester thereof and apharmaceutically acceptable binder comprising the steps of

-   -   (a) dissolving the pharmaceutically acceptable binder in a        solvent,    -   (b) mixing the dissolved binder with 5-ASA to form a wet mass,    -   (c) extruding the wet mass into granules, and    -   (d) drying the granules upon evaporation of the solvent,        wherein the new, surprising and advantageous feature is that the        solvent is comprised of at least 50% w/w water.

Subsequently, the granules are milled and sieved.

In a preferred embodiment of the invention, the solvent comprises morethan 85% w/w water. In another preferred embodiment the solventcomprises more than 95% w/w. Most preferred, the solvent is free oforganic solvent. The solvent may optionally comprise one or moreadditives.

In another preferred embodiment, the resulting granules, after beingmilled, have a particle size distribution measured by sieve analysiswhere the main fraction is from 850 μm to 1000 μm. The holes in theextruder may be varied in order to obtain the desired particle size.More than 75%, preferably more than 85% and most preferably more than90% of the granules have a particle size from 850 μm to 1000 μm.

The ratio of the binder, e.g. polyvinylpyrrolidone, to the activeingredient, 5-ASA, in the resulting granules is preferably up to 8:100,more preferably up to 6.5:100 and most preferably up to 5:100. Otherbinders, if desired, may replace polyvinylpyrrolidone. Binders that maybe considered for the granules are selected from the group comprisingderivatives of cellulose, polyvinylpyrrolidone, pregelatinizedcornstarch or any other suitable binder. Such binders may be used indifferent amounts relative to 5-ASA.

In another aspect the present invention utilises the first fundamentalaspect in a method for the preparation of prolonged release tabletsuseful for the treatment of ulcerative colitis or Crohn's disease,comprising the steps of

-   -   (a) preparing granules from 5-aminosalicylic acid or a        pharmaceutically acceptable salt or ester thereof and up to 8%        by weight (solids content, based on the 5-aminosalicylic acid)        of a binder in a solvent comprising at least 50% w/w water.    -   (b) applying onto said granules an polymer composition,        comprising a solution in an organic solvent of a        pharmaceutically acceptable polymer material thereby to provide        coated granules upon evaporation of the solvent,    -   (c) mixing the coated granules with pharmaceutically acceptable        tablet excipients, and    -   (d) forming tablets from the resulting mixture.

The granules are preferably prepared according to the first aspect ofthe present invention i.e. the granules are extruded, dried, milled andsieved in one continuous process.

In one embodiment of the method, the granules are dried in a fluid bed.

In another embodiment, the coating material is a cellulose derivative,such as ethyl cellulose.

In a further embodiment, the tablet excipients comprise a tabletcarrier, such as microcrystalline cellulose, a lubricant, such asmagnesium stearate and optionally further excipients such as talc.

INDUSTRIAL APPLICABILITY 1. General Considerations

As each tablet or dose contains a relative large amount of material,large amounts of material must be handled in the production line. Thegranules may be manufactured batchwise or in a continuous process, i.e.the granules may be extruded, dried, milled and sieve in one continuousprocess.

The production line for the production of granules in a continuousprocess should be able to handle the following production steps (seealso FIG. 4).

-   -   1. Wet mixing of 5-ASA with a solution of a binder, such as        polyvinylpyrrolidone (Povidone) in water (50% w/w or more)    -   2. Extrusion    -   3. Drying    -   4. Milling    -   5. Sieving

Because it is a continuous process the equipment should be built in sucha way that it is possible to control the flow of the differentingredients into the process. By controlling the flow it is possible toget the right ratio between the ingredients through the whole process.

2. Production of Granules Comprising PVP

Polyvinylpyrrolidone (PVP) is dissolved in an solvent, e.g. 100% w/wwater. 5-ASA and the aqueous solution of PVP are mixed and added to theextruder. Alternatively, 5-ASA and the aqueous solution of PVP may bemixed in the extruder. The wet mass consisting of 5-ASA and PVP isextruded through a screen and allowed to fall into a device for dryingof the wet granules.

The aqueous solvent is preferably water of a suitable quality, but maycontain additives, such as chelating agents, antioxidants, reducingagents, buffers and pH adjusting agents.

Advantageously the extruder comprises a screen, which has numerouscircular holes with a diameter of between 0.5 and 1.3 mm, preferably 0.9mm. The thickness of the screen is between 0.9 and 2.0 mm, preferably,the thickness of the screen is 1.5 mm. The holes can have the samecross-section through the screen or be tapered in either direction.Preferably, the holes are tapered, each hole having a cross-section atthe inlet side of the sheet that is larger than the cross-section at theoutlet side of the screen, the preferred outlet diameter is 0.9 mm andthe preferred inlet diameter is 0.95 mm.

Advantageously the drying device is preferably a fluid bed. However,other possibilities known by the skilled person may also be used.

If a fluid bed is used, it may be designed in such a way that thedwelling time in the fluid bed is approximately 2½ hour. However,shorter or longer times are also within the present invention. The fluidbed is advantageously separated in two parts where the granules in thefirst part are dried on the surface to avoid that they stick together.In this part a random mixing of the granules take place. In the secondpart of the fluid bed the final drying takes place and the granules areguided through the fluid bed by the pattern of holes in the bottomplate.

When the granules are dry they are discharged from the fluid bed andtransferred to a mill to reduce the length of the granules. The millingprocess generates a small amount of fines that has to be removed bysieving before the granules are ready for coating. At this stage a sieveanalysis, as described earlier may be performed.

3. Coating

The resulting granules are coated. The granules may be coated in anycoating device applicable to the process. The skilled person wouldreadily know which devices would be suitable for the present process,such as for example a fluid bed system, e.g. a Kugelcoater. The granulesare preferably coated with a polymer dissolved in a suitable solvent forthe polymer, preferably an organic solvent such as acetone.

In order to be able to determine the amount of polymer that has to beapplied to the granules the surface area is measured. Based on a knowncorrelation between the amount of polymer per surface area and thedissolution rate profile, the amount of polymer needed can be predictedfrom the measured surface area of the granules. The smoother the surfaceof the granules, the smaller the surface area, and the smaller thesurface area, the smaller the amount of polymer needed. Any agglomeratesformed during the coating step are removed by sieving.

The selected coating polymer is mostly dependent on the desired releasepattern. It may be chosen from rate-limiting barrier-materials, e.g.enteric or delayed coating material, such as polymethacrylate,commercial available in the form Eudragit™ S, Eudragit™ RL and Eudragit™RS, respectively. When a semi-permeable polymer is used, ethyl celluloseis the most preferred polymer.

4. Mixing

The coated granules are mixed with the remaining tablet excipients in aconventional dry mixing process.

Tablet excipients may include any suitable pharmaceutically acceptablecarriers which are well known to the skilled person, e.g. lactose, maizestarch, potato starch, and lubricants, e.g. magnesium stearate and talc.A preferred carrier constituent is microcrystalline cellulose.

The Pentasa® tablets produced according to the conventional methodcomprise as tablet excipients microcrystalline cellulose, magnesiumstearate and talc. Tablets according to the present invention mayadvantageously be comprise the same excipients.

5. Compressing and Dedusting

The final blend of coated granules and excipients is compressed intotablets in any suitable tabletting machine, such as on a rotarytabletting machine and the tablets are dedusted. The tablets may be ofany conceivable size or weight, e.g. 100 mg-10 g, more preferably 500 mgto 3 g.

6. The Active Ingredient

5-aminosalicylic acid or any salt or ester thereof is the activeingredient in the granules. The salts of 5-ASA may be acid additionsalts, in particular the hydrochloride, but any pharmaceuticallyacceptable, non-toxic organic or inorganic acid may be used.

Also salts formed with the carboxylic acid group may be used. Asexamples may be mentioned alkali metal salts (K, Na), alkaline earthmetal salts (Ca, Mg), but again any pharmaceutically acceptable,non-toxic salt may be used. The Na- and Ca-salts are preferred.

In DE patent application No. 2712394 (AU application No. 7723548),incorporated herein by reference, a number of esters of ortho-, meta-and para-salicylic acid are disclosed. The disclosed meta- (or 5-)aminosalicylic esters and a number of related esters are also applicableas active ingredient in the composition produced according to theinvention.

Applicable esters are e.g. straight chain or branched C₁-C₁₉ alkylesters, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl,hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, andstearyl, etc., straight chain or branched C₁-C₁₉ alkenyl esters, e.g.vinyl, allyl, undecenyl, oleyl, linolenyl, etc., C₃-C₄ cycloalkylesters, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, etc., aryl esters, e.g. phenyl, toluyl,xylyl, naphthyl, etc., alicyclic esters, e.g. menthyl, etc., or aralkylesters, e.g. benzyl, phenethyl, etc.

Generally speaking the proper selection of the active ingredient dependson the selected type of formulation, the disease pattern, especially thesite and type of the disease, and the desired release of the activeingredient.

The physical state and solubility characteristics of the 5-ASAderivatives must be taken into account when selecting a suitable carriercomposition for the ingredient.

The preferred active ingredient at present is the free acid,5-aminosalicylic acid.

The effective oral dose depends on the extent of the disease and foradults it usually amounts to 0.5-1.0 g four times a day. Generally about20 mg/kg body weight of 5-ASA or a salt or ester thereof (calculated as5-ASA) will be the recommended initial daily dosage subject toadjustment in accordance with the observed results of the treatment.

While the preferred coating agent is ethyl cellulose other coatingagents may also be used, provided they secure the desired releasepattern. In particular a number of other cellulose derivatives must beassumed to be applicable. At present, the preferred release pattern is acontinuous release following arrival in the small intestine. Thisrelease was originally designed as to enable the tablets, e.g. Pentasa®,to be effective both against Crohn's disease and ulcerative colitis.

However, in case it should be desirable to secure an early release inthe small bowel (in the case of Crohn's disease) or a delayed releaseuntil arrival in the colon (in the case of ulcerative colitis), therelease pattern can be controlled by varying different parameters of thetablet as discussed in WO 81/02671, which is hereby incorporated byreference.

EXAMPLE 1

Production of Pentasa tablets (existing isopropanol based granulationprocess) Pentasa ® slow-release tablets 500 mg Quantity per batch Nameof the constituents (155000 tablets) Specifications Active ingredient:5-aminosalicylic acid 77.5 kg Ferring Other Ingredients Povidone 3875 g± 10% Ph. Eur. Isopropyl alcohol 17.3 kg Ph. Eur. Purified water 1550 gPh. Eur. Ethylcellulose q.s Ph. Eur. Acetone q.s Ph. Eur. Magnesiumstearate 155 g Ph. Eur. Talc 1395 g Ph. Eur. Microcrystalline ad 116250g Ph. Eur. cellulose Equipment for the Production: Equipment FunctionNICA Mixer M6L Granulation NICA Extruder E 220 Extrusion AEROMATIC FluidBed Dryer Drying FREWITT MG 8 Oscillator Oscillation MOGENSEN Typ 0254Sizer Sieving HÜTTLIN Kugelcoater HKC 200 Coating or HÜTTLIN KugelcoaterHKC 400 PRODIMA Mixer AC-HLR 500 Mixing KILIAN T 300 or TablettingKORSCH Pharmapress 250Manufacturing Steps

-   -   The manufacture of Pentasa® Slow-release tablets is performed in        10 steps.        Step 0: Start Routine of the Equipment and Ingredients    -   All the equipment is checked for cleanliness before use.        Step 1:Weighing    -   5-aminosalicylic acid is weighed out and fed into the mixer.        Step 2:Granulation    -   The granulation liquid (povidone dissolved in a mixture of        purified water and 2-propanol) is prepared and added during        mixing. The mixing is continued for a fixed time after addition        of the granulation liquid.        Step 3:Extrusion    -   The granulated mass is extruded into pellets in the same        procedure (Screen 1.0×1.0 (diameter×thickness of the screen)).        Step 4:Drying    -   The granules are transferred to a fluid bed dryer and dried.        Step 5:Sieving    -   The dried pellets are sifted on a Mogensen sieve (tilted sieve).        Granules which pass the screen size of 0.8 mm are discarded or        can be collected for reprocessing stored in air-tight, labelled        containers. Granules which do not pass the screen size of 1.8 mm        are discarded.        Step 6:Coating    -   The granules are coated in a Kugelcoater (fluid bed system) with        a liquid consisting of ethylcellulose in acetone. If any lumps        are formed the granules are sifted on a Mogensen sieve (tilted        sieve).        Step 7:Mixing    -   The coated granules, the filler/binder (microcrystalline        cellulose) and the lubricants (magnesium stearate and talc) are        transferred to the mixer and thoroughly mixed.        Step 8:Compression    -   The final blend of coated granules and lubricants is compressed        into tablets on a rotary tabletting machine.        Step 9:Dedusting    -   The tablets are dedusted.        Step 10:Packaging    -   The slow-release tablets are placed in a labelled bulk container        and stored in quarantine until released by the Quality Control        Department.

-   FIGS. 1A-3A shows enlarged photos of granules from three different    batches obtained by the existing method.

EXAMPLE 2 The Effect of Variation in Different Parameters of the Process

In the present example dry and wet material were mixed in an Erweka AR400E Intensive mixer. The extrusion was performed in a Niro FielderExtruder E140. Unless otherwise stated, the screen used in the extrudercontains holes with the dimension 0.9×0.9 mm. (diameter×thickness of thescreen). For the sieve analysis is used a Retch Vibro sieve.

At first, 3 critical parameters of the process, the PVP content, thewater content and the speed of the mixer were investigated in a 2³factorial analysis:

Low level High level Factor a PVP 3% w/w 8% w/w Factor b Water 0% w/w 6%w/w Factor c Impeller 33 rpm 66 rpm

The resulting granules were evaluated as a yield after sieving in therange 0.850-1.0 mm. The test was repeated 5 times and the results showthat both the content of water and PVP have influence on the yield inthe range 0.850-1.0 mm. The speed of the impeller has no influence onthe yield in the given range as shown in table 1:

TABLE 1 Results from the 2³ factorial experiment showing the % yieldafter sieving in the range 0.850-1.0 mm Trial Mean SD (1) 63.40 3.62 a60.48 2.22 b 70.22 2.12 ab 80.66 3.74 c 60.68 3.59 ac 66.38 4.52 bc70.44 2.21 abc 80.22 3.00

In order to optimise the content of water and PVP in the extrudedgranules a new trial was conducted in 2 repetitions. The water plusisopropyl alcohol (IPA) was kept constant at 35% w/w, and the watercontent varied between 6, 12 and 18% w/w. The PVP content was variedbetween 5, 6.5 and 8% w/w.

The results are shown in table 2 and show that the higher content ofwater, the higher yield was obtained. If the content of PVP wasincreased to 8% w/w, the yield decreased due to agglomerates.

Encouraged by the above results, yet another trial was set up toinvestigate what would happens if the water content was furtherincreased and the IPA omitted. The solvent (water+IPA) content was againkept constant at 35% w/w, while the water content was varied between 24,30 and 35% w/w. I addition, solvent contents of 30 and 33% w/w, free ofIPA were used in the trial. The PVP content was varied between 5 and6.5% w/w

As shown in table 2, if the amount of water is increased to 30% w/w andthe IPA omitted, a higher yield of granules is obtained.

TABLE 2 % Yield as a function of water content and amount of PVP. % w/wPVP % w/w Water 5 6.5 8 6 72.8 78.1 82.9 12 78.0 82.7 48.3 18 80.3 82.742.9 24 80.0 85.5 30 84.8 89.6 30 no IPA 93.7 94.2 33 no IPA 94.9 Toowet 35 no IPA Too wetThe Effect of the Screen on the Resulting Granules

In order to optimise the holes in the extruder, different screens weretried out. The results shown in table 3, indicate that for the selectedwet mass, 0.9×0.9 mm (diameter×thickness of screen) was the best choicefor obtaining granules with a particle size of 850-1000 um.

TABLE 3 Particle size distribution as a function of hole dimensions inthe screen. Particle Hole dimensions mm size μm 1.0 x 1.2 1.0 x 1.0 0.9x 1.0 0.9 x 0.9 >1180 2.0% 1.7% 1.0% 0.7% 1000-1180 78.2%  57.0%  4.5%1.4%  850-1000 17.1%  39.2%  58.6%  92.8%  <850  2.7% 2.2% 35.9%  5.2%

In a repeated trial, the narrow and reproducible particle sizedistribution of the granules prepared according to a preferred method ofthe present invention was investigated and shown in table 4.

TABLE 4 Particle size distribution of batches prepared according to apreferred method of the present invention. Batch % (w/w) no.: >1180 μm850 μm < x < 1180 μm <850 μm moisture 732902 2.2 92.8 4.7 0.56 7331011.1 94.2 5.7 1.14 733102 0.9 94.2 5.2 0.99 733103 0.8 94.1 5.4 0.53733104 1.0 94.2 5.3 0.46 733107 2.2 94.5 4.6 0.50 Mean 1.4 94.0 5.2 0.51SD 0.65 0.60 0.42 0.04 RDS 48 0.64 8.1 8.3

The moisture content was also of an acceptable level.

For practical use of the screen in a production facility, a thickness ofthe screen of 1.5 mm is preferred.

The strength of the granules was evaluated by processing the granules 1hour in a laboratory fluid bed (STREA). The strength was compared togranules produced in accordance with the existing production facilitiesfor producing Pentasa®. As shown in table 5, the strength is increasedin the granules produced in accordance with the present invention:

TABLE 5 showing the % of granules with a particle size between 850μm-1000 μm before and after processing the granules in a laboratoryfluid bed for 1 h. Batch No. Before Strea After Strea Difference Present733102 94.2 95.2 −1.0 invention 733103 93.9 94.1 −0.2 733104 93.9 94.6−0.7 733107 94.8 93.9 0.9 Existing EJGU838C 57.5 54.9 2.6 processEJGU838D 63.5 60.9 2.6 EJGU837G 68.5 61.9 6.6 EJGU838H 53.3 44.6 8.7

EXAMPLE 3 Production of 5-ASA Comprising Tablets (Water BasedGranulation Process)

The new manufacturing process for the 5-ASA tablets can be divided into11 steps (FIG. 4):

-   -   1. Preparation of granulation liquid    -   2. Granulation of 5-ASA with water and PVP    -   3. Extrusion    -   4. Fluid bed drying    -   5. Milling    -   6. Sieving    -   7. Coating    -   8. Sieving    -   9. Air purging    -   10. Dry blending with excipients    -   11. Compression to tablets

Equipment for the production NICA Extruder E220 Extrusion Rotostat T05Blending NIRO Fluid bed dryer Drying Quadro Comil U10 Milling Mogensensieve Sieving Huttling Kugelcoater HKC 400 Coating Prodima rotationsieve Sieving Purging unit Air purge Prodima Mixer AC-HLR 1200 Drymixing Kilian T300-32 Tabletting

Step 1:

For one batch of granulation liquid 118.4 kg of water is filled into aMüller drum. The mixer is put into position and started. 32 kg ofpolyvinylpyrrolidone (PVP) is slowly sprinkled onto the water and themixer is allowed to run a fixed time until all PVP is dissolved.

Step 2 and 3:

5-ASA is placed in a vibrating Prodima hopper and by the use of aconveyor the 5-ASA is transported up to a weight belt feeder dosing the5-ASA into the continuous Niro line. In the first part of the Niro linethe 5-ASA and the water solution of PVP are mixed to a wet mass beforebeing transported into the extruder. After extrusion of the wet mass of5-ASA and PVP/water through a screen mesh 0.9 mm, the granules falldirectly into the fluid bed dryer.

Step 4:

The fluid bed dryer is divided into two main sections. In the firstsection, the granules are dried on the surface to prevent them fromsticking together. In this section of the fluid bed, a random mixing ofthe granules takes place. After a certain residence time, the granulesare moved into the second part of the dryer where the actual dryingtakes place. In the second part of the dryer the granules are guided bythe use of the drying air through the dryer (special pattern of holes inthe gill plate). When the granules are dry they are allowed to fall intoa drum placed under the fluid bed. The fluid bed is constructed in sucha way that the overall dwelling time in the fluid bed is approximately2½ hour.

Due to the property of being a continuous process, the batch size isdefined by how long time the equipment is running. The equipment istherefore built in a way making it possible to control the flow of thedifferent ingredients going into the process. In order to document thedrying process, the results from loss on drying are shown in table 6.

TABLE 6 Loss on drying (% moisture in the granules after drying) Müllerdrum AAA137 AAA138 AAA139 AAA140 1 0.40 0.34 0.37 0.37 2 0.37 0.30 0.400.40 3 0.46 0.29 0.37 0.37 4 0.33 0.40 0.40 0.33 5 0.37 0.39 n.a. 0.37 6n.a. 0.29 n.a. 0.33 7 n.a. 0.34 n.a. 0.33 8 n.a. 0.37 n.a. 0.39 Mean0.37 0.39 0.39 0.36 (n.a. = not available)

Step 5:

The drums containing the dry granules are placed upside down on top ofthe mill and the granules are gently milled using a screen, which willonly break the granules that are too long. After passing the mill, thegranules are allowed to fall into a drum. FIGS. 5A-7A show enlargedphotos of three different batches of granules produced according to thepresent invention. A difference in shape, conformity and homogeneity canbe clearly seen when compared to the granules produced according to theexisting process (FIGS. 1A-3A).

Step 6:

Due to the fact that the milling process generates a small amount ofundersized granules, the granules are sieved using a Mogensen vibrationsieve. Granules, which pass the screen 0.8-mm, are discarded or can becollected for reprocessing stored in airtight, labelled containers.Results from sieve analysis of the milled and sieved granules are shownin FIGS. 5B-7B.

Step 7:

200 kg of sieved granules are coated in a Kugel coater (fluid bedsystem) with a coating liquid consisting of ethyl cellulose dissolved inacetone.

In order to be able to determine the right amount of polymer necessaryto apply on the granules to get the desirable dissolution rate profile,the surface area of the granules are measured prior to the coatingprocess. The prediction of the quantity of polymer that is necessary toapply on the granules has been developed based on the fact that there isa correlation between the amount of polymer per surface area and thedissolution rate of the granules. After finishing the coating process,the coated granules are loaded into a drum for further processing.

Step 8:

After the coating process, the coated granules are sieved in a Prodimarotation sieve. Large lumps are discarded.

Step 9:

After sieving the batch of coated granules, they are divided into twodrums for purging with compressed air or nitrogen. The granules arepurged for 6-14 hours. This purging process is necessary to reduce theamount of residual solvent (acetone) in the coated granules.

Results from test of residual solvent in granules prepared according tothe existing method and according to the new method are shown in table7. As seen from table 7 the content of residual solvent has been reducedconsiderably in the granules manufactured according to the new method.This may ascribed to the fact that these granules have a smoothersurface than the granules prepared by the existing method, hence theamount of coating material necessary is reduced.

TABLE 7 Residual solvent in coated Pentasa ® granules. Amount of AcetoneAmount of Acetone Existing method before purging after purging withPentasa ® granules with Air/Nitrogen Air/Nitrogen Batch no. (ppm) (ppm)GIGC 905 5277 2607 GIGC 906 5556 1870 GIGC 907 4310 1798 Amount ofAcetone Amount of Acetone New method before purging after purging withPentasa ® granules with Air/Nitrogen Air/Nitrogen Batch no. (ppm) (ppm)AAF 333 965 331 AAF 322 1125 402 AAF 327 1020 492

Step 10

178.56 kg coated Pentasa granules are weighed out and loaded into theProdima blender together with 69.34-kg microcrystalline cellulose. Aftermixing for 210 seconds the blender is stopped. 0.335 kg magnesiumstearate and 3.02 kg Talc are added to the blend and the ingredients aremixed for 90 seconds. The blend will give 335.000 tablets.

After mixing the blend is discharged into Müller drums ready forcompression.

Step 11

The final blend of coated granules and excipients is compressed on arotary tabletting machine. Weight of the tablets: 750 mg. Dedusting ofthe tablets is performed as an in line process with the tablettingmachine. After dedusting the tablets, they are loaded into bulkcontainers holding approximately 30.000 tablets each.

The method of the present invention leads to an increased overall yieldof 5-ASA tablets from the same amount of ingredients as obtained by useof the existing method. The properties of the tablets from 10 batchesprepared according to the present invention are shown in table 8.

As can be seen from these tables, the tablets prepared according to thepresent invention comply with criteria for acceptance of the tablets andthe overall yield is about 85.5% compared to 69.2 for the existingmethod.

Dissolution rate profiles for Pentasa® tablets are shown in FIG. 8

FIG. 9 shows the results of samples taken in the blender to documenthomogeneity of the blend.

TABLE 8 Test results from 10 batches of Pentasa ® tablets Content WeightTablet Hardness Weight Height Disintegration uniformity variation AssayFriability Batch N mg mm sek mg mg mg/tabl % AAH025 98 749.1 4.10 10520.0 515.8 507.0 0.03 491.4 498.9 AAH026 100 751.5 4.04 11 523.9 509.2503.8 0.05 497.8 498.4 AAH027 80 750.8 3.97 5 512.3 495.7 492.4 0.20486.6 487.8 AAH028 99 751.4 4.04 8 514.5 498.4 489.3 0.07 483.7 486.7AAH030 97 748.1 4.00 8 511.6 495.1 497.1 0.03 486.0 487.2 AAH031 92750.9 3.98 9 509.9 508.9 502.2 0.04 481.4 496.8 AAH032 96 751.6 3.97 11507.3 499.9 495.9 0.08 485.9 492.6 AAH033 99 753.1 4.02 9 516.6 506.4504.4 0.03 495.3 499.0 AAH034 103 749.1 4.00 9 513.6 500.9 495.0 0.04467.3 488.4 AAH035 97 749.8 4.08 7 531.1 493.8 491.8 0.04 487.9 485.284-112 735-765 3.80-4.20 ≦5 min 450-550 ≦0.8% Acceptance average averageaverage average 425-575 425-575 average average criteria of 10 of 10 of10 of 6 each tablet each tablet of 20 of 10 Result Comply Comply ComplyComply Comply Comply Comply Comply

1. A method for the preparation of prolonged-release tablets of5-aminosalicyclic acid (5-ASA) or pharmaceutically acceptable salt orester thereof, comprising: (a) mixing polyvinyl pyrrolidone as apharmaceutically acceptable binder in a solvent; the solvent consistingof at least 85% w/w water and up to 15% w/w organic solvent; (b) mixingthe solvent-binder mixture with 5-ASA to form a wet mass consisting of5-ASA, binder, and solvent, in which the solvent is present at up to 35%by weight of the weight of 5-ASA; (c) extruding the wet mass to formstrong, smooth granules comprising 5-ASA and binder; (d) drying thegranules in a continuous fluid bed dryer to produce dried granules inwhich: the weight ratio of the pharmaceutically acceptable binder to5-ASA is up to 6.5:100; and more than 85% of the dried granules have aparticle size of 850 to 1000 μm; (e) coating the dried granules with asolution of a pharmaceutically acceptable coating material in a coatingorganic solvent, wherein the amount of the coating composition isadjusted to the specific surface area of the dried granules to achievethe desired dissolution rate profile; (f) purging coating organicsolvent from the coated granules; (g) mixing the coated granules withone or more pharmaceutically acceptable tablet excipients; and (h)forming tablets from the resulting mixture.
 2. The method of claim 1,wherein the coating material is selected to provide for a dissolutionrate-limiting barrier on the granules.
 3. The method of claim 2, whereinthe coating material comprises ethyl cellulose.
 4. The method of claim1, wherein the tablet excipients comprise microcrystalline cellulose. 5.The method of claim 2, wherein the barrier is semipermeable.
 6. Themethod of claim 1, wherein more than 90% of the dried granules have aparticle size of 850 to 1000 μm.